We propose to investigate the interaction between the peripheral metabolic signal, insulin, and central reward circuits, specifically addressing insulin's effects on sucrose consumption and motivation to work for a sucrose reward. Preliminary data indicate insulin may depress firing in dopamine (DA) neurons in the ventral tegmental area (VTA), by activating the PIS kinase signaling cascade linked with its receptors on these neurons, and that this leads to decreased reward responding. However, these data also implicate another, non-DA, neuronal type in the VTA. It is important to know if this is a direct effect on the DA neurons, or if it is mediated by another cell type. A primary candidate is the population of GABA neurons that exert tonic inhibition on the DA neurons. Insulin may inhibit activity of the DA neurons themselves, or may enhance activity of the GABA neurons, or both. We propose to address this problem by 1) identifying whether the insulin-receptive, non-DA neurons in the VTA are GABAergic, and whether insulin activates its signaling pathway in these neurons; and 2) determining insulin's inhibitory effects on GABA- induced sucrose intake. Relevance: This project will investigate the organization of the brain's reward system with respect to food intake. The obesity epidemic may be largely due to the abundance of cheap, high-calorie, rewarding foods, so it is important to determine how the brain may "overreact" to these foods, in a manner similar to drug addiction. Results from this study will be applicable both to the obesity problem and the problem of drug abuse. [unreadable] [unreadable] [unreadable]